A 44 amino acid peptide having growth hormone releasing activity has recently been reported [Guillemin et al., Science 218, 585 (1982)]. The peptide, isolated from a human tumor of the pancreas and designated hpGRF, has the structure H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser- Ala-Arg-Lys-Leu-Leu-Gpn-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu -Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH.sub.2.
At approximately the same time, a shortened form of the foregoing peptide, also having growth hormone releasing activity, was also reported [Rivier et al., Nature 300, 276 (1982)]. This peptide terminates as a free carboxylic acid and differs from the foregoing by the absence of the C-terminal tetrapeptide amide -Arg-Ala-Arg-Leu-NH.sub.2.
A study of growth hormone release factor (GRF) (whether the 44 amino acid form or the shortened 40 amino acid form) has established (as its name implies) its efficacy in stimulating pituitary release of growth hormone. It has also been suggested (Rivier et al., supra) that GRF activity is retained even upon further shortening of the C-terminal region of the peptide. Thus, Rivier et al. prepared and tested a number of shortened GRF analogs. When compared in vitro with the parent hpGRF(1-40)-OH, Rivier et al. state that the following exhibited similar (within a factor of two) potencies: hpGRF(1-29)-NH.sub.2, hpGRF(1-32)-NH.sub.2, hpGRF(1-39)-NH.sub.2, and hpGRF(1-40)-NH.sub.2. Moreover, they state that "full intrinsic activity is observed in hpGRF(1-27)-NH.sub.2 which possesses 10-20% of the potency of hpGRF(1-40)-OH." (page 277).
Rivier et al. further examined the importance of the methionine-27 residue in the overall sequence. They converted hpGRF(1-40)-OH to the corresponding methionine sulfoxide derivative and, upon in vitro testing, conclude that "partial oxidation of methionine-27 to methionine sulfoxide leads to a significant loss of activity (about 2% of that of the parent compound) . . . " (page 276, FIG. 1 legend).
The implicit conclusions of the Rivier et al. studies suggest (1) that much of the C-terminal portion of the hpGRF(1-40)-OH is of only limited importance to the growth hormone releasing activity of the molecule and (2) that the methionine in position 27 is of great importance to such activity.
It has now been discovered that, contrary to the Rivier et al. conclusions, the growth hormone releasing activity of hpGRF is not dependent upon the presence of methionine in position 27. It is to a class of analogs of hpGRF bearing substitutions of the methionine residue that this invention is directed. The compounds of this invention exhibit, upon in vivo administration, high levels of growth hormone releasing activity.